Substituted isoindoline-1,3-dione derivatives

ABSTRACT

This invention relates to novel substituted isoindoline-1,3-dione derivatives and pharmaceutically acceptable salts thereof. More specifically, the invention relates to novel substituted isoindoline-1,3-dione derivatives that are analogues of apremilast. This invention also provides compositions comprising a compound of this invention and a carrier and the use of disclosed compounds and compositions in methods of treating diseases and conditions that are beneficially treated by administering apremilast.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 61,268,953, filed Jun. 18, 2009. The entire teaches of the aboveapplication is incorporated herein.

BACKGROUND OF THE INVENTION

Many current medicines suffer from poor absorption, distribution,metabolism and/or excretion (ADME) properties that prevent their wideruse or limit their use in certain indications. Poor ADME properties arealso a major reason for the failure of drug candidates in clinicaltrials. While formulation technologies and prodrug strategies can beemployed in some cases to improve certain ADME properties, theseapproaches often fail to address the underlying ADME problems that existfor many drugs and drug candidates. One such problem is rapid metabolismthat causes a number of drugs, which otherwise would be highly effectivein treating a disease, to be cleared too rapidly from the body. Apossible solution to rapid drug clearance is frequent or high dosing toattain a sufficiently high plasma level of drug. This, however,introduces a number of potential treatment problems such as poor patientcompliance with the dosing regimen, side effects that become more acutewith higher doses, and increased cost of treatment. A rapidlymetabolized drug may also expose patients to undesirable toxic orreactive metabolites.

Another ADME limitation that affects many medicines is the formation oftoxic or biologically reactive metabolites. As a result, some patientsreceiving the drug may experience toxicities, or the safe dosing of suchdrugs may be limited such that patients receive a suboptimal amount ofthe active agent. In certain cases, modifying dosing intervals orformulation approaches can help to reduce clinical adverse effects, butoften the formation of such undesirable metabolites is intrinsic to themetabolism of the compound.

In some select cases, a metabolic inhibitor will be co-administered witha drug that is cleared too rapidly. Such is the case with the proteaseinhibitor class of drugs that are used to treat HIV infection. The FDArecommends that these drugs be co-dosed with ritonavir, an inhibitor ofcytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsiblefor their metabolism (see Kempf, D. J. et al., Antimicrobial agents andchemotherapy, 1997, 41(3): 654-60). Ritonavir, however, causes adverseeffects and adds to the pill burden for HIV patients who must alreadytake a combination of different drugs. Similarly, the CYP2D6 inhibitorquinidine has been added to dextromethorphan for the purpose of reducingrapid CYP2D6 metabolism of dextromethorphan in a treatment ofpseudobulbar affect. Quinidine, however, has unwanted side effects thatgreatly limit its use in potential combination therapy (see Wang, L etal., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67;and FDA label for quinidine at www.accessdata.fda.gov).

In general, combining drugs with cytochrome P450 inhibitors is not asatisfactory strategy for decreasing drug clearance. The inhibition of aCYP enzyme's activity can affect the metabolism and clearance of otherdrugs metabolized by that same enzyme. CYP inhibition can cause otherdrugs to accumulate in the body to toxic levels.

A potentially attractive strategy for improving a drug's metabolicproperties is deuterium modification. In this approach, one attempts toslow the CYP-mediated metabolism of a drug or to reduce the formation ofundesirable metabolites by replacing one or more hydrogen atoms withdeuterium atoms. Deuterium is a safe, stable, non-radioactive isotope ofhydrogen. Compared to hydrogen, deuterium forms stronger bonds withcarbon. In select cases, the increased bond strength imparted bydeuterium can positively impact the ADME properties of a drug, creatingthe potential for improved drug efficacy, safety, and/or tolerability.At the same time, because the size and shape of deuterium areessentially identical to those of hydrogen, replacement of hydrogen bydeuterium would not be expected to affect the biochemical potency andselectivity of the drug as compared to the original chemical entity thatcontains only hydrogen.

Over the past 35 years, the effects of deuterium substitution on therate of metabolism have been reported for a very small percentage ofapproved drugs (see. e.g. Blake, M J et al. J Pharm Sci, 1975,64:367-91; Foster, A B, Adv Drug Res 1985, 14:1-40 (“Foster”); Kushner,D J et al. Can J Physiol Pharmacol 1999, 79-88; Fisher, M B et al, CurrOpin Drug Discov Devel, 2006, 9:101-09 (“Fisher”)). The results havebeen variable and unpredictable. For some compounds deuteration causeddecreased metabolic clearance in vivo. For others, there was no changein metabolism. Still others demonstrated increased metabolic clearance.The variability in deuterium effects has also led experts to question ordismiss deuterium modification as a viable drug design strategy forinhibiting adverse metabolism (see Foster at p. 35 and Fisher at p.101).

The effects of deuterium modification on a drug's metabolic propertiesare not predictable even when deuterium atoms are incorporated at knownsites of metabolism. Only by actually preparing and testing a deuterateddrug can one determine if and how the rate of metabolism will differfrom that of its non-deuterated counterpart. See, for example, Fukuto etal. (J. Med. Chem. 1991, 34, 2871-76). Many drugs have multiple siteswhere metabolism is possible. The site(s) where deuterium substitutionis required and the extent of deuteration necessary to see an effect onmetabolism, if any, will be different for each drug.

Apremilast, also known as(+)-N-[2-[1(S)-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]acetamide,is a PDE4 inhibitor and also acts to reduce TNF-α levels. Apremilast isin clinical trials for the treatment of psoriasis, plaque-typepsoriasis, refractory psoriasis, cutaneous sarcoidosis, psoriaticarthritis, Behçet's Disease, prurigo nodularis, cutaneous lupus, anduveitis, among others.

Common adverse events associated with PDE4 inhibitors generally includeheadache, nausea, emesis and gastrointestinal disturbances.

It would be desirable to provide a compound that has the beneficialactivities of apremilast and other benefits, e.g., reduced adverse sideeffects, with a decreased metabolic liability, to further extend itspharmacological effective life, enhance patient compliance and,potentially, to decrease population pharmacokinetic variability and/ordecrease its potential for dangerous drug-drug interactions.

SUMMARY OF THE INVENTION

This invention relates to novel substituted isoindoline-1,3-dionederivatives and pharmaceutically acceptable salts thereof.

More specifically, the invention relates to novel substitutedisoindoline-1,3-dione derivatives that are analogues of apremilast. Thisinvention also provides compositions comprising a compound of thisinvention and a carrier and the use of disclosed compounds andcompositions in methods of treating diseases and conditions that arebeneficially treated by administering apremilast.

DETAILED DESCRIPTION OF THE INVENTION

The term “treat” means decrease, suppress, attenuate, diminish, arrest,or stabilize the development or progression of a disease (e.g., adisease or disorder delineated herein), lessen the severity of thedisease or improve the symptoms associated with the disease.

“Disease” means any condition or disorder that damages or interfereswith the normal function of a cell, tissue, or organ.

It will be recognized that some variation of natural isotopic abundanceoccurs in a synthesized compound depending upon the origin of chemicalmaterials used in the synthesis. Thus, a preparation of apremilast willinherently contain small amounts of deuterated isotopologues. Theconcentration of naturally abundant stable hydrogen and carbon isotopes,notwithstanding this variation, is small and immaterial as compared tothe degree of stable isotopic substitution of compounds of thisinvention. See, for instance, Wada E et al., Seikagaku 1994, 66:15;Gannes L Z et al., Comp Biochem Physiol Mol Integr Physiol 1998,119:725.

In the compounds of this invention any atom not specifically designatedas a particular isotope is meant to represent any stable isotope of thatatom. Unless otherwise stated, when a position is designatedspecifically as “H” or “hydrogen”, the position is understood to havehydrogen at its natural abundance isotopic composition. Also unlessotherwise stated, when a position is designated specifically as “D” or“deuterium”, the position is understood to have deuterium at anabundance that is at least 3340 times greater than the natural abundanceof deuterium, which is 0.015% (i.e., at least 50.1% incorporation ofdeuterium).

The term “isotopic enrichment factor” as used herein means the ratiobetween the isotopic abundance and the natural abundance of a specifiedisotope.

In other embodiments, a compound of this invention has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium), at least 5500 (82.5%deuterium incorporation), at least 6000 (90% deuterium incorporation),at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97%deuterium incorporation), at least 6600 (99% deuterium incorporation),or at least 6633.3 (99.5% deuterium incorporation).

The term “isotopologue” refers to a species in which the chemicalstructure differs from a specific compound of this invention only in theisotopic composition thereof.

The term “compound,” when referring to a compound of this invention,refers to a collection of molecules having an identical chemicalstructure, except that there may be isotopic variation among theconstituent atoms of the molecules. Thus, it will be clear to those ofskill in the art that a compound represented by a particular chemicalstructure containing indicated deuterium atoms, will also contain lesseramounts of isotopologues having hydrogen atoms at one or more of thedesignated deuterium positions in that structure. The relative amount ofsuch isotopologues in a compound of this invention will depend upon anumber of factors including the isotopic purity of deuterated reagentsused to make the compound and the efficiency of incorporation ofdeuterium in the various synthesis steps used to prepare the compound.However, as set forth above the relative amount of such isotopologues Intoto will be less than 49.9% of the compound. In other embodiments, therelative amount of such isotopologues in toto will be less than 47.5%,less than 40%, less than 32.5%, less than 25%, less than 17.5%, lessthan 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% ofthe compound.

The invention also provides salts of the compounds of the invention.

A salt of a compound of this invention is formed between an acid and abasic group of the compound, such as an amino functional group, or abase and an acidic group of the compound, such as a carboxyl functionalgroup. According to another embodiment, the compound is apharmaceutically acceptable acid addition salt.

The term “pharmaceutically acceptable,” as used herein, refers to acomponent that is, within the scope of sound medical judgment, suitablefor use in contact with the tissues of humans and other mammals withoutundue toxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. A “pharmaceuticallyacceptable salt” means any non-toxic salt that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention. A “pharmaceutically acceptable counterion”is an ionic portion of a salt that is not toxic when released from thesalt upon administration to a recipient.

Acids commonly employed to form pharmaceutically acceptable saltsinclude inorganic acids such as hydrogen bisulfide, hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, aswell as organic acids such as para-toluenesulfonic acid, salicylic acid,tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylicacid, fumaric acid, gluconic acid, glucuronic acid, formic acid,glutamic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonicacid, carbonic acid, succinic acid, citric acid, benzoic acid and aceticacid, as well as related inorganic and organic acids. Suchpharmaceutically acceptable salts thus include sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephthalate, sulfonate, xylene sulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycolate, maleate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and othersalts. In one embodiment, pharmaceutically acceptable acid additionsalts include those formed with mineral acids such as hydrochloric acidand hydrobromic acid, and especially those formed with organic acidssuch as maleic acid.

The pharmaceutically acceptable salt may also be a salt of a compound ofthe present invention having an acidic functional group, such as acarboxylic acid functional group, and a base. Exemplary bases include,but are not limited to, hydroxide of alkali metals including sodium,potassium, and lithium; hydroxides of alkaline earth metals such ascalcium and magnesium; hydroxides of other metals, such as aluminum andzinc; ammonia, organic amines such as unsubstituted orhydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine;tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-OH—(C₁-C₆)-alkylamine), such asN,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine;pyrrolidine; and amino acids such as arginine, lysine, and the like.

The compounds of the present invention (e.g., compounds of Formula I),may contain an asymmetric carbon atom, for example, as the result ofdeuterium substitution or otherwise. As such, compounds of thisinvention can exist as either individual enantiomers, or mixtures of thetwo enantiomers. Accordingly, a compound of the present invention mayexist as either a racemic mixture or a scalemic mixture, such as amixture containing predominantly one stereoisomer, or as individualrespective stereoisomers that are substantially free from anotherpossible stereoisomer. The term “substantially free of otherstereoisomers” as used herein means less than 25% of otherstereoisomers, preferably less than 10% of other stereoisomers, morepreferably less than 5% of other stereoisomers and most preferably lessthan 2% of other stereoisomers are present. Methods of obtaining orsynthesizing an individual enantiomer for a given compound are known inthe art and may hbe applied as practicable to final compounds or tostarling material or intermediates.

Unless otherwise indicated, when a disclosed compound is named ordepicted by a structure without specifying the stereochemistry and hasone or more chiral centers, it is understood to represent all possiblestereoisomers of the compound.

The term “stable compounds,” as used herein, refers to compounds whichpossess stability sufficient to allow for their manufacture and whichmaintain the integrity of the compound for a sufficient period of timeto be useful for the purposes detailed herein (e.g., formulation intotherapeutic products, intermediates for use in production of therapeuticcompounds, isolatable or storable intermediate compounds, treating adisease or condition responsive to therapeutic agents).

“D” and “d” both refer to deuterium. “Stereoisomer” refers to bothenantiomers and diastereomers. “Tert” and “t-” each refer to tertiary.“US” refers to the United States of America.

“Substituted with deuterium” refers to the replacement of one or morehydrogen atoms with a corresponding number of deuterium atoms.

Throughout this specification, a variable may be referred to generally(e.g., “each R”) or may be referred to specifically (e.g., R¹, R², R³,etc.). Unless otherwise indicated, when a variable is referred togenerally, it is meant to include all specific embodiments of thatparticular variable.

Therapeutic Compounds

The present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:R¹ is selected from CH₃, CH₂D, CHD₂, and CD₃;R² is selected from the group consisting of methyl, isopropyl,cyclopentyl, cyclopropyl, 2-furanyl, trifluoromethyl, methoxymethyl,aminomethyl, dimethylaminomethyl, dimethylamino-1-ethyl,1-dimethylamino-ethyl, and 2-dimethylamino-ethyl, wherein R² isoptionally substituted with deuterium;R³ is selected from CH₃, CH₂D, CHD₂, CD₃, CF₃, CHF₂, CH₂F, CDF₂, andCD₂F;R⁴ is an ethyl group substituted with zero to five deuterium, or is acyclopentyl group substituted with zero to nine deuterium;X is selected from CH₂, CHD, CD₂, and C═O;each of Y^(1a), Y^(1b), Y², Y³, Y⁴, Y⁵, Y⁷ and Y⁸ is independentlyselected from H and D; andY⁶ is selected from Cl, H, and D;provided that if R¹ is CH₃; R² is not substituted with deuterium; R³ isCH₃, CF₃, CHF₂, or CH₂F; R⁴ is an ethyl group not substituted withdeuterium or a cyclopentyl group not substituted with deuterium; X isCH₂ or C═O; and Y is Cl or H;then at least one of Y^(1a), Y^(1b), Y², Y³, Y⁴, Y⁵, Y⁷ and Y⁸ is D.

In one embodiment, the compound of Formula I is a compound of FormulaII:

or a pharmaceutically acceptable salt thereof, wherein:R¹ is selected from CH₃ and CD₃;R² is selected from the group consisting of methyl, isopropyl,cyclopentyl, cyclopropyl, 2-furanyl, trifluoromethyl, methoxymethyl,aminomethyl, dimethylaminomethyl, dimethylamino-1-ethyl,1-dimethylamino-ethyl, and 2-dimethylamino-ethyl, wherein R² isoptionally substituted with deuterium;R³ is selected from CH₃, CD₃, CF₃, CHF₂, CH₂F, CDF₂, and CD₂F;R⁴ is selected from CH₂CH₃, CD₇CD₃, CD₂CH₃, and CH₂CD₃; andeach Y is independently selected from H and D;provided that if R¹ is CH₃; R² is not substituted with deuterium; R³ isCH₃, CF₃, CHF₂, or CH₂F; and R⁴ is CH₂CH₃;then at least one Y is D.

In one embodiment of Formula I or Formula II, R¹ is CH₃ or CD₃.

In one embodiment of Formula I or Formula II, R² is CH₃ or CD₃.

In one embodiment of Formula I or Formula II, R³ is CH₃ or CD₃.

In one embodiment of Formula I or Formula II, Y⁶, Y⁷ and Y⁸ are thesame. In one aspect. Y⁶, Y⁷ and Y⁸ are each hydrogen.

In one embodiment of Formula I or Formula II, Y^(1a) and Y^(1b) are thesame. In one aspect, Y^(1a) and Y^(1b) are both hydrogen. In anotheraspect, Y^(1a) and Y^(1b) are both deuterium.

In one embodiment of Formula I or Formula II, Y³, Y⁴ and Y⁵ are thesame. In one aspect, Y³, Y⁴ and Y⁵ are each hydrogen.

In one embodiment of Formula I or Formula II, R⁴ is CD₂CD₃. In oneembodiment of Formula I or Formula II, R² is CH₃ or CD₃; R³ is CH₃ orCD₃; Y⁶, Y⁷ and Y⁸ are the same; Y^(1a) and Y^(1b) are the same; and Y³,Y⁴ and Y⁵ are the same.

In one embodiment of Formula I or Formula II, R¹ is CH₃ or CD₃; R² isCH₃ or CD₃; R³ is CH₃ or CD₃; R⁴ is CD₂CD₃; Y⁶, Y⁷ and Y⁸ are the same;Y^(1a) and Y^(1b) are the same; and Y³, Y⁴ and Y⁵ are the same.

In one embodiment, the compound of Formula I is a compound of FormulaIa, having predominantly the (S) configuration at the carbon attached toY²;

or a pharmaceutically acceptable salt thereof, wherein the remainingvariables are as defined for Formula I.

In one embodiment, the compound of Formula Ia is substantially free ofother stereoisomers.

In one embodiment, the compound of Formula I is a compound of FormulaIb, having predominantly the (R) configuration at the carbon attached toY²:

or a pharmaceutically acceptable salt thereof, wherein the remainingvariables are as defined for Formula I.

In one embodiment, the compound of Formula Ib is substantially free ofother stereoisomers.

In one embodiment of Formula Ia or Formula Ib, R¹ is CH₃ or CD₃.

In one embodiment of Formula Ia or Formula Ib, R² is CH₃ or CD₃.

In one embodiment of Formula Ia or Formula Ib, R³ is CH₃ or CD₃.

In one embodiment of Formula Ia or Formula Ib, Y⁶, Y⁷ and Y⁸ are thesame. In one aspect, Y⁶, Y⁷ and Y⁸ are each hydrogen.

In one embodiment of Formula Ia or Formula Ib, Y^(1a) and Y^(1b) are thesame. In one aspect, Y^(1a) and Y^(1b) are both hydrogen. In anotheraspect, Y^(1a) and Y^(1b) are both deuterium.

In one embodiment of Formula Ia or Formula Ib, Y³, Y⁴ and Y⁵ are thesame. In one aspect, Y³, Y⁴ and Y⁵ are each hydrogen.

In one embodiment of Formula Ia or Formula Ib, R⁴ is CD₂CD₃.

In one embodiment of Formula Ia or Formula Ib, R¹ is CH₃ or CD₃; R² isCH₃ or CD₃; R³ is CH₃ or CD₃; R⁴ is CD₂CD₃; Y⁶, Y⁷ and Y⁸ are the same;Y^(1a) and Y^(1b) are the same; and Y³, Y⁴ and Y⁵ are the same.

In one embodiment, the compound of Formula I is selected from the groupconsisting of:

or a pharmaceutically acceptable salt of any of the foregoing.

In one embodiment, the compound of Formula I is selected from the groupconsisting of:

or a pharmaceutically acceptable salt of any of the foregoing.

In one embodiment, the compound is a compound of Formula Ia and isselected from the group consisting of:

or a pharmaceutically acceptable salt of any of the foregoing.

One embodiment provides a compound that is predominantly the (S)enantiomer of compound 100, 101, 102, 103, 104, 105, 106, 107, 108, 109,110, 111, or 112 or a pharmaceutically acceptable salt of any of theforegoing.

One embodiment provides a compound that is predominantly the (S)enantiomer of compound 113, 114, 115, 116 or a pharmaceuticallyacceptable salt of any of the foregoing.

One embodiment provides a compound that is predominantly the (R)enantiomer of compound 100, 101, 102, 103, 104, 105, 106, 107, 108, 109,110, 111, or 112 or a pharmaceutically acceptable salt of any of theforegoing.

One embodiment provides a compound that is predominantly the (R)enantiomer of compound 113, 114, 115, 116 or a pharmaceuticallyacceptable salt of any of the foregoing.

In another set of embodiments, any atom not designated as deuterium inany of the embodiments set forth above for a compound of Formula I,I(a), or I(b) is present at its natural isotopic abundance.

The synthesis of compounds of Formula I can be readily achieved bysynthetic chemists of ordinary skill. Relevant procedures andintermediates are disclosed, for instance in Man, H. W. et al., Journalof Medicinal Chemistry (2009), 52(6), 1522-1524; Muller, G. W. et al.Journal of Medicinal Chemistry (1996), 39(17), 3238-3240; WO2006/025991;AU2006/200033; WO2001/034606; U.S. Pat. No. 6,020,358; and U.S. Pat. No.6,667,316.

Such methods can be carried out utilizing corresponding deuterated andoptionally, other isotope-containing reagents and/or intermediates tosynthesize the compounds delineated herein, or invoking standardsynthetic protocols known in the art for introducing isotopic atoms to achemical structure. Certain intermediates can be used with or withoutpurification (e.g., filtration, distillation, sublimation,crystallization, trituration, solid phase extraction, andchromatography).

EXEMPLARY SYNTHESIS

Scheme 1 depicts a general route to preparing compounds of Formula I,according to the general methods of Man, H W; et al. Journal ofMedicinal Chemistry (2009), 52(6), 1522-1524. Thus, appropriatelysubstituted aldehyde 10 is treated with lithium hexamethyldisilazide,followed by lithium dimethylsulfone and boron trifluoride etherate toafford racemic amine 11, which has a stereocenter at the carbon attachedto Y². If desired, racemic amine 11 may be resolved via treatment withan enantiopure acid in methanol. For example, treatment of racemic amine11 with N-acetyl-L-leucine affords amine 11 as the S enantiomer, whiletreatment with N-acetyl-D-leucine affords amine 11 as the R enantiomer.Amine 11 may be used as the racemate, as the S enantiomer, or as the Renantiomer to yield compounds of Formula I upon treatment with anhydride12 either neat or in a solvent such as acetic acid. One skilled in theart will appreciate that the use of appropriately deuteratedintermediates and reagents in Scheme 1 results in the production ofcompounds of Formula I bearing various patterns of deuteriumsubstitution.

Scheme 2 depicts a preparation of aldehyde 10, which is a usefulstarting material for Scheme 1. As generally described in Li, Juren; etal. Hecheng Huaxue (1993), 1(4), 333-40, appropriately-deuterated diol13 is treated with appropriately-deuterated ethyl bromide 14 under phasetransfer conditions to afford phenol 15. Reimer-Tiemann reaction ofphenol 15 with chloroform provides aldehyde 16. Deuterated reagents andsolvents may be useful in this step to maximize levels of isotopicincorporation. Alternatively, the tetrabutylammonium bromide conditionsgenerally described by Li, Ying-chun; et al. Yingyong Huagong (2004),33(1), 26-27 may be used to convert 15 to 16. According to the generalmethods of Kiehlmann, E.; et al., Organic Preparations and ProceduresInternational (1982), 14(5), 337-42, treatment of 16 withappropriately-deuterated dimethylsulfate 17 provides desiredintermediate 10.

For example, commercially-available dimethyl-d6 sulfate may be used asreagent 17 in Scheme 2 to ultimately produce compounds of Formula Iwherein R³ is CD₃. In another example, commercially-availablebromoethane-d5 may be used as reagent 14 in Scheme 2 to ultimatelyproduce compounds of Formula I wherein R⁴ is —CD₂CD₃. Similarly,commercially-available bromoethane-2,2,2-d3 and bromoethane-1,1-d2 wouldalso be of use in Scheme 2 to ultimately produce compounds of Formula Ibearing various other patterns of deuterium substitution at R⁴.

Scheme 3 depicts a preparation of intermediate 12a, an example ofintermediate 12 wherein X is C═O, and intermediate 12b, an example ofintermediate 12 wherein X is CH₂, CHD, or CD₂. Nitration of anhydridescaffold 18 is well known in the literature, for example in patentapplications WO 2005051870, CN 1740138, and CN 1405143; and inliterature articles including Chen, Zhi-min; et al. Hecheng Huaxue(2004). 12(2), 167-169, 173; Zhu, Zhi-jia; et al. Huaxue Shiji (2003).25(5), 306, 308; Ma, S. L.; et al. Polish Journal of Chemistry (2002),76(4), 511-517; and Culhane, P. J.; et al. Organic Syntheses (1927), 7,no pp. given. Use of appropriately-deuterated starting materials andreagents will produce deuterated versions of 19. According to thegeneral methods described in US patent application US 2008234359,hydrogenation of 19 in the presence of palladium on carbon affords amine20, which is then treated with appropriately-deuterated acetic anhydride21 to provide intermediate 12a. According to the general methods ofWamser, C. C.; et al. J. Org. Chem. (1976), 41(17), 2929-31,intermediate 12a may be reduced with zinc and acid to provideintermediate 12b. Commercially-available DCl, acetic acid-d4, and aceticanhydride-d6 may be used in the final step to provide alternate patternsof deuterium incorporation.

For example, commercially-available 3-aminophthalic acid may be used inScheme 3 as intermediate 20 to ultimately produce compounds of Formula Iwherein Y⁶, Y⁷, and Y⁸ are all hydrogen. In another example,commercially-available acetic anhydride-d6 may be used in Scheme 3 asreagent 21 to ultimately yield compounds of Formula I wherein R² is CD₃.In yet another example, commercially-available phthalic-d4 anhydride maybe used in Scheme 3 as anhydride 18 to ultimately provide compounds ofFormula I wherein Y⁶, Y⁷, and Y⁸ are all deuterium.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds.

Compositions

The invention also provides compositions comprising an effective amountof a compound of Formula I (e.g., including any of the formulae herein),or a pharmaceutically acceptable salt of said compound; and anacceptable carrier. The carrier(s) are “acceptable” in the sense ofbeing compatible with the other ingredients of the formulation and, inthe case of a pharmaceutically acceptable carrier, not deleterious tothe recipient thereof in an amount used in the medicament.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of this invention include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

The pharmaceutical compositions of the invention include those suitablefor oral, rectal, nasal, topical (including buccal and sublingual),vaginal or parenteral (including subcutaneous, intramuscular,intravenous and intradermal) administration. In certain embodiments, thecompound of the formulae herein is administered transdermally (e.g.,using a transdermal patch or iontophoretic techniques). Otherformulations may conveniently be presented in unit dosage form, e.g.,tablets, sustained release capsules, and in liposomes, and may beprepared by any methods well known in the art of pharmacy. See, forexample, Remington: The Science and Practice of Pharmacy, LippincottWilliams & Wilkins, Baltimore, Md. (20th ed. 2000).

Such preparative methods include the step of bringing into associationwith the molecule to be administered ingredients such as the carrierthat constitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredients with liquid carriers, liposomes orfinely divided solid carriers, or both, and then, if necessary, shapingthe product.

In certain embodiments, the compound is administered orally.Compositions of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, sachets, or tabletseach containing a predetermined amount of the active ingredient; apowder or granules; a solution or a suspension in an aqueous liquid or anon-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oilliquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatincapsules can be useful for containing such suspensions, which maybeneficially increase the rate of compound absorption.

In the case of tablets for oral use, carriers that are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried cornstarch. When aqueoussuspensions are administered orally, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring and/or coloring agents may be added.

Compositions suitable for oral administration include lozengescomprising the ingredients in a flavored basis, usually sucrose andacacia or tragacanth; and pastilles comprising the active ingredient inan inert basis such as gelatin and glycerin, or sucrose and acacia.

Compositions suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example, scaled ampules and vials, and may be stored ina freeze dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tablets.

Such injection solutions may be in the form, for example, of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to techniques known in the art using suitabledispersing or wetting agents (such as, for example, Tween; 80) andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are mannitol, water, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose, any blandfixed oil may be employed including synthetic mono- or diglycerides.Fatty acids, such as oleic acid and its glyceride derivatives are usefulin the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant.

The pharmaceutical compositions of this invention may be administered inthe form of suppositories for rectal administration. These compositionscan be prepared by mixing a compound of this invention with a suitablenon-irritating excipient which is solid at room temperature but liquidat the rectal temperature and therefore will melt in the rectum torelease the active components. Such materials include, but are notlimited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art. See, e.g.: Rabinowitz J D and Zaffaroni A C, U.S. Pat. No.6,803,031, assigned to Alexza Molecular Delivery Corporation.

Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For topicalapplication topically to the skin, the pharmaceutical composition shouldbe formulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax, and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier. Suitable carriers include, but are not limitedto, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esterswax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. Thepharmaceutical compositions of this invention may also be topicallyapplied to the lower intestinal tract by rectal suppository formulationor in a suitable enema formulation. Topically-transdermal patches andiontophoretic administration are also included in this invention.

Application of the patient therapeutics may be local, so as to beadministered at the site of interest. Various techniques can be used forproviding the subject compositions at the site of interest, such asinjection, use of catheters, trocars, projectiles, pluronic gel, stents,sustained drug release polymers or other device which provides forinternal access.

Thus, according to yet another embodiment, the compounds of thisinvention may be incorporated into compositions for coating animplantable medical device, such as prostheses, artificial valves,vascular grafts, stents, or catheters. Suitable coatings and the generalpreparation of coated implantable devices are known in the art and areexemplified in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. Thecoatings are typically biocompatible polymeric materials such as ahydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethyleneglycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.The coatings may optionally be further covered by a suitable topcoat offluorosilicone, polysaccharides, polyethylene glycol, phospholipids orcombinations thereof to impart controlled release characteristics in thecomposition. Coatings for invasive devices are to be included within thedefinition of pharmaceutically acceptable carrier, adjuvant or vehicle,as those terms are used herein.

According to another embodiment, the invention provides a method ofcoating an implantable medical device comprising the step of contactingsaid device with the coating composition described above. It will beobvious to those skilled in the art that the coating of the device willoccur prior to implantation into a mammal.

According to another embodiment, the invention provides a method ofimpregnating an implantable drug release device comprising the step ofcontacting said drug release device with a compound or composition ofthis invention. Implantable drug release devices include, but are notlimited to, biodegradable polymer capsules or bullets, non-degradable,diffusible polymer capsules and biodegradable polymer wafers.

According to another embodiment, the invention provides an implantablemedical device coated with a compound or a composition comprising acompound of this invention, such that said compound is therapeuticallyactive.

According to another embodiment, the invention provides an implantabledrug release device impregnated with or containing a compound or acomposition comprising a compound of this invention, such that saidcompound is released from said device and is therapeutically active.

Where an organ or tissue is accessible because of removal from thepatient, such organ or tissue may be bathed in a medium containing acomposition of this invention, a composition of this invention may bepainted onto the organ, or a composition of this invention may beapplied in any other convenient way.

In another embodiment, a composition of this invention further comprisesa second therapeutic agent.

The second therapeutic agent may be selected from any compound ortherapeutic agent known to have or that demonstrates advantageousproperties when administered with a compound having the same mechanismof action as apremilast. Such agents include those indicated as beinguseful in combination with apremilast, including but not limited to,those agents useful for the treatment of psoriasis, includingplaque-type psoriasis and refractory psoriasis; sarcoidosis, includingcutaneous sarcoidosis; psoriatic arthritis; Behçet's Disease; prurigonodularis; lupus, including cutaneous lupus; and uveitis, among others.

In one embodiment, the second therapeutic agent is an agent useful forthe treatment of psoriasis or sarcoidosis.

In another embodiment, the invention provides separate dosage forms of acompound of this invention and one or more of any of the above-describedsecond therapeutic agents, wherein the compound and second therapeuticagent are associated with one another. The term “associated with oneanother” as used herein means that the separate dosage forms arepackaged together or otherwise attached to one another such that it isreadily apparent that the separate dosage forms are intended to be soldand administered together (within less than 24 hours of one another,consecutively or simultaneously).

In the pharmaceutical compositions of the invention, the compound of thepresent invention is present in an effective amount. As used herein, theterm “effective amount” refers to an amount which, when administered ina proper dosing regimen, is sufficient to treat (therapeutically orprophylactically) the target disorder. For example, to reduce theseverity, duration or progression of the disorder being treated, preventthe advancement of the disorder being treated, cause the regression ofthe disorder being treated, or enhance or improve the prophylactic ortherapeutic effect(s) of another therapy.

The interrelationship of dosages for animals and humans (based onmilligrams per meter squared of body surface) is described in Freireichet al., Cancer Chemother. Rep, 1966, 50: 219. Body surface area may beapproximately determined from height and weight of the patient. See,e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970,537.

In one embodiment, an effective amount of a compound of this inventioncan range from about 0.2 to 2000 mg per treatment. In more specificembodiments the range is from about 2 to 1000 mg or from 4 to 400 mg ormost specifically from 20 to 200 mg per treatment. Treatment typicallyis administered at a rate of between 0.625 to 1.25 ng/kg/min. Theinfusion rate can be increased in increments of no more than 1.25ng/kg/min per week for the first four weeks and then no more than 2.5ng/kg/min per week for the remaining duration of infusion.

Effective doses will also vary, as recognized by those skilled in theart, depending on the diseases treated, the severity of the disease, theroute of administration, the sex, age and general health condition ofthe patient, excipient usage, the possibility of co-usage with othertherapeutic treatments such as use of other agents and the judgment ofthe treating physician. For example, guidance for selecting an effectivedose can be determined by reference to the prescribing information forapremilast.

For pharmaceutical compositions that comprise a second therapeuticagent, an effective amount of the second therapeutic agent is betweenabout 20% and 100% of the dosage normally utilized in a monotherapyregime using just that agent. Preferably, an effective amount is betweenabout 70% and 100% of the normal monotherapeutic dose. The normalmonotherapeutic dosages of these second therapeutic agents are wellknown in the art. See, e.g., Wells et al. eds. Pharmacotherapy Handbook,2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDRPharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition,Tarascon Publishing, Loma Linda, Calif. (2000), each of which referencesare incorporated herein by reference in their entirety.

It is expected that some of the second therapeutic agents referencedabove will act synergistically with the compounds of this invention.When this occurs, it will allow the effective dosage of the secondtherapeutic agent and/or the compound of this invention to be reducedfrom that required in a monotherapy. This has the advantage ofminimizing toxic side effects of either the second therapeutic agent ofa compound of this invention, synergistic improvements in efficacy,improved ease of administration or use and/or reduced overall expense ofcompound preparation or formulation.

Methods of Treatment

In another embodiment, the invention provides a method of inhibitingPDE4 in a subject, comprising administering to the subject a compound ofFormula I herein or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a method of reducing TNF-αlevels in a subject, comprising administering to the subject a compoundof Formula I herein or a pharmaceutically acceptable salt thereof.

According to another embodiment, the invention provides a method oftreating a disease that is beneficially treated by apremilast comprisingthe step of administering to a patient in need thereof an effectiveamount of a compound of Formula I or a pharmaceutically acceptable saltthereof or a composition of this invention. Such diseases are well knownin the art and are disclosed in, but not limited to the followingpatents and published applications: WO2006/025991; AU2006/200033;WO2001/034606; U.S. Pat. No. 6,020,358; and U.S. Pat. No. 6,667,316.

Such diseases include, but are not limited to, septic shock, sepsis,endotoxic shock, hemodynamic shock and sepsis syndrome, post ischemicreperfusion injury, malaria, mycobacterial infection, meningitis;psoriasis, including plaque-type psoriasis and refractory psoriasis;sarcoidosis, including cutaneous sarcoidosis; psoriatic arthritis;Behçet's Disease; prurigo nodularis; lupus, including cutaneous lupus;uveitis; congestive heart failure, fibrotic disease, cachexia, graftrejection, cancer, autoimmune disease, opportunistic infections in AIDS,rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, otherarthritic conditions, Crohn's disease, ulcerative colitis, multiplesclerosis, systemic lupus erythrematosis, ENL in leprosy, radiationdamage, hyperoxic alveolar injury, undesirable angiogenesis,inflammatory disease, arthritis, inflammatory bowel disease, aphthousulcers, asthma, adult respiratory distress syndrome, and AIDS.

In one particular embodiment, the method of this invention is used totreat psoriasis or sarcoidosis.

Methods delineated herein also include those wherein the patient isidentified as in need of a particular stated treatment. Identifying apatient in need of such treatment can be in the judgment of a patient ora health care professional and can be subjective (e.g. opinion) orobjective (e.g. measurable by a test or diagnostic method).

In another embodiment, any of the above methods of treatment comprisesthe further step of co-administering to the patient one or more secondtherapeutic agents. The choice of second therapeutic agent may be madefrom any second therapeutic agent known to be useful forco-administration with apremilast. The choice of second therapeuticagent is also dependent upon the particular disease or condition to betreated. Examples of second therapeutic agents that may be employed inthe methods of this invention are those set forth above for use incombination compositions comprising a compound of this invention and asecond therapeutic agent.

In particular, the combination therapies of this invention includeco-administering a compound of Formula I, or a pharmaceuticallyacceptable salt thereof and a second therapeutic agent for treatment ofthe following conditions: psoriasis, including plaque-type psoriasis andrefractory psoriasis; sarcoidosis, including cutaneous sarcoidosis;psoriatic arthritis; Behçet's Disease; prurigo nodularis; lupus,including cutaneous lupus; and uveitis.

The term “co-administered” as used herein means that the secondtherapeutic agent may be administered together with a compound of thisinvention as part of a single dosage form (such as a composition of thisinvention comprising a compound of the invention and an secondtherapeutic agent as described above) or as separate, multiple dosageforms. Alternatively, the additional agent may be administered prior to,consecutively with, or following the administration of a compound ofthis invention. In such combination therapy treatment, both thecompounds of this invention and the second therapeutic agent(s) areadministered by conventional methods. The administration of acomposition of this invention, comprising both a compound of theinvention and a second therapeutic agent, to a patient does not precludethe separate administration of that same therapeutic agent, any othersecond therapeutic agent or any compound of this invention to saidpatient at another time during a course of treatment.

Effective amounts of these second therapeutic agents are well known tothose skilled in the art and guidance for dosing may be found in patentsand published patent applications referenced herein, as well as in Wellset al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange,Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia2000, Deluxe Edition, Tarascon Publishing. Loma Linda, Calif. (2000),and other medical texts. However, it is well within the skilledartisan's purview to determine the second therapeutic agent's optimaleffective-amount range.

In one embodiment of the invention, where a second therapeutic agent isadministered to a subject, the effective amount of the compound of thisinvention is less than its effective amount would be where the secondtherapeutic agent is not administered. In another embodiment, theeffective amount of the second therapeutic agent is less than itseffective amount would be where the compound of this invention is notadministered. In this way, undesired side effects associated with highdoses of either agent may be minimized. Other potential advantages(including without limitation improved dosing regimens and/or reduceddrug cost) will be apparent to those of skill in the art.

In yet another aspect, the invention provides the use of a compound ofFormula I or a pharmaceutical salt thereof alone or together with one ormore of the above-described second therapeutic agents in the manufactureof a medicament, either as a single composition or as separate dosageforms, for treatment in a patient of a disease, disorder or symptom setforth above. Another aspect of the invention is a compound of Formula Ior a pharmaceutical salt thereof for use in the treatment in a patientof a disease, disorder or symptom thereof delineated herein.

EXAMPLES Example 1 Synthesis of(S)—N-(2-(1-d-2-(Methylsulfonyl)-1-(3-(ethoxy-d₅)-4-(methoxy-d₃)phenyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide(Compound 113a)

Step 1. Ethyl 3-hydroxy-4-(methoxy-d₃)-benzoate (23). Commerciallyavailable ester 22 (10 g, 55 mmol) was mixed with CD₃I (99 atom % D,Cambridge Isotopes; 8.1 g, 55 mol) and K₂CO₃ (7.59 g) in DMF and stirredat room temperature over a weekend. LCMS showed three peaks with massesconsistent with starting material (20%), the desired monoalkylated 23(55%) product and the bisalkylated (23%) by-product. The reaction wasfiltered through a pad of Celite, washing with EtOAc, and the filtrateconcentrated to almost dryness. The residue was dissolved in CH₂Cl₂ (300mL) and the solution was washed with water (5×50 mL), brine, dried(Na₂SO₄) and concentrated. The crude product was purified bychromatography on silica gel eluting with EtOAc/heptane (1:9 to 1:6)then further triturated from heptane to give 4.1 g (36%) of the desired23.

Step 2. Ethyl 3-(ethoxy-d₅)-4-(methoxy-d₃)-benzoate (24). 23 (4.1 g, 20mmol) was dissolved in DMF (10 mL) and K₂CO₃(2.5 g) and CD₃CD₂Br (99atom % D, Cambridge Isotopes; 4.7 g, 41 mmol) were added. The reactionflask was sealed and stirred at room temperature for 24 hr. LCMS showedthe reaction was complete. The mixture was filtered through a pad ofCelite, washing with MTBE. The filtrate was concentrated to removevolatiles and water (100 mL) was added. The solids were collected undervacuum and washed with water (50 mL). The solid was re-dissolved in MTBE(200 mL) and the solution was washed with brine, dried (Na₂SO₄) andconcentrated to give approximately 3.8 g (81%) of 24 (purityapproximately 90% by LCMS).

Step 3. (3-Ethoxy-d₅)-4-(methoxy-d₃)-phenyl)-1,1-d₂-methanol (25). 24(3.8 g, 16.3 mmol) was dissolved in MTBE (50 mL) and LiAlD₄ (98 atom %D, Cambridge Isotopes; 0.7 g, 17 mmol) was added. The reaction mixturewas stirred at room temperature overnight. LCMS indicated the reactionwas complete. Aqueous NH₄Cl (20 mL) was added cautiously to quench thereaction and the mixture was filtered through a pad of Celite. Thephases were separated and the aqueous phase was extracted with EtOAc(2×20 mL). The combined organic phases were dried (Na₂SO₄) andconcentrated to give 2.8 g of 25 as a light yellow oil. This materialwas used directly in the next step.

Step 4. 3-(Ethoxy-d₅)-4-(methoxy-d₃)-benzaldehyde-d (10a). 25 (2.8 g, 16mmol) was dissolved in EtOAc (30 mL). MnO₂(14 g, 160 mmol) was added andthe dark mixture was stirred at room temperature overnight. LCMS showedcomplete consumption of the starting material. The mixture was passedthrough a pad of Celite, washing with EtOAc, and the filtrate wasconcentrated to give a yellow oil. The oil was purified viachromatography on silica gel eluting with 20% EtOAc/heptane to give 2.05g (68% for 2 steps) of 10a as a white solid.

Step 5.1-(3-(Ethoxy-d₅)-4-(methoxy-d₃)-phenyl)-1-d-2-(methylsulfonyl)ethanamine(11a). Methyl sulfone (1 g, 10.7 mmol) was suspended in THF (70 mL) andcooled in an acetone/dry ice bath to below −70° C. n-BuLi (2.5 M inhexanes, 4.6 mL, 11.5 mmol) was added and the mixture stirred 30minutes. In a separate flask, a solution of 10a (1.9 g, 10.0 mmol) inTHF (20 mL) was cooled to 0° C. Lithium hexamethyldisilazide (LHMDS) (1Min THF, 12 mL) was added. After 15 minutes boron trifluoride etherate(2.8 mL, 22 mmol) was added and stirring was continued for another 5minutes. This solution was then added to the methyl sulfone/n-BuLisolution, with cooling in an acetone/dry ice bath to below −70° C. via asyringe. An exotherm was observed. This mixture was allowed to warm toroom temperature and was stirred overnight. After cooling in anice-water bath. K₂CO₃ (8 g) was added followed by water (50 mL). Thelayers were separated and the aqueous phase was extracted with EtOAc(2×20 mL). The combined organic solution was dried (Na₂SO₄) andconcentrated to give a sticky oil. MTBE (30 mL) and aqueous HCl (4N, 30mL) were added and the mixture stirred at room temperature for 2 hr togive a clear biphasic solution. The phases were separated and theorganic solution extracted with aqueous HCl (4 N, 25 mL). To thecombined aqueous phases was added aqueous NaOH (24%) until pH>12. Theaqueous phase was extracted with EtOAc (3×50 mL), the organic phaseswere dried (Na₂SO₄), and concentrated to give a yellow solid. The solidwas suspended in MTBE (20 mL) and stirred for one hour. Filtration undervacuum gave 1.2 g (36%) of 11a.

Step 6.(S)-1-(3-(Ethoxy-d₅)-4-(methoxy-d₃)-phenyl-1-d-2-(methylsulfonyl)ethanamineN-acetyl leucine salt ((S)-11a). 11a (1.2 g, 4.25 mmol) was mixed withN-acetyl-L-leucine (0.44 g, 2.55 mmol) in MeOH (10 mL). This mixture washeated at 70° C. for 3 hr then stirred at room temperature overnight.The solid was collected by vacuum filtration and suspended in MeOH (15mL). The mixture was stirred at 70° C. for 2 hr, then at roomtemperature overnight. The solid was collected and the MeOH triturationwas repeated. A 600-mg portion (31%) of (S)-11a was isolated with >99%ee.

Step 7.(S)—N-(2-(1-d-1-(3-(Ethoxy-d₅)-4-(methoxy-d₃)-phenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide(Compound 113a). (S)-11a (380 mg, 0.88 mmol) was mixed with known 12a(200 mg, 1 mmol; see US 20080234359) in acetic acid (6 mL) and heated atreflux for 24 hr to drive the reaction to completion. The mixture wasconcentrated and the colorless oil was re-dissolved in EtOAc (100 mL).The solution was washed with saturated aqueous NaHCO₃ (20 mL), dried(Na₂SO₄) and concentrated. The crude product was purified by columnchromatography on an Analogix system eluting with 0-3% MeOH/CH₂Cl₂ toprovide 360 mg (87%) of 113a. ¹H-NMR (300 MHz, CDCl₃): δ 1.58 (s, 1H),2.27 (s, 3H), 2.87 (s, 3H), 3.72 (d, J=14.3 1H), 4.55 (d, J=14.5, 1H),6.84 (d, J=9.8, 1H). 7.11 (d, J=9.2, 2H), 7.49 (d, J=6.5, 1H), 7.66 (s,J=7.7, 1H), 8.77 (d, J=7.7, 1H), 9.46 (s, 1H). ¹³C-NMR (75 MHz, CDCl₃):δ 24.97, 41.67, 54.47, 111.45, 112.38, 115.14, 118.25, 120.28, 124.99,129.18, 131.07, 136.14, 137.66, 148.70, 167.51, 169.16. HPLC (method: 50mm 3 μm Waters Atlantis T3 2.1 column—gradient method 5-95% ACN+0.1%formic acid in 14 min with 4 min hold at 95% ACN+0.1% formic acid;wavelength: 305 nm): retention time: 5.96 min; 99.5% purity. MS (M+H):470.3. Elemental Analysis (C₂₂H₁₅D₉N₂O₇S.H₂0): Calculated: C=54.20,H=5.38, N=5.75. Found: C=54.15, H=4.98, N=5.60.

Example 2 Synthesis of (S)—N(2-(2-(Methylsulfonyl)-1-(3-(ethoxy-d₅)-4-(methoxy-d₂)phenyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide(Compound 107a)

Step 1. 3-Hydroxy-4-(methoxy-d₃)-benzaldehyde (27). Commerciallyavailable 3,4,-dihydroxy-benzaldehyde 26 (10 g, 80 mmol) was dissolvedin DMF (50 mL). K₂CO₃ (10 g) was added and the solution was cooled in anice-water bath. CD₃I (99 atom % D. Cambridge Isotopes; 12.4 g, 84 mmol)was slowly added, then the reaction was stirred at room temperatureovernight. The reaction was diluted with EtOAc (200 mL) and filteredthrough a pad of Celite. The filtrate was concentrated to give a darkoil. EtOAc (150 mL) and water (50 mL) were added and the layers wereseparated. The aqueous phase was adjusted to pH 6 by the slow additionof 1N HCl and the mixture was extracted with EtOAc (2×100 mL). Thecombined organic solution was dried (Na₂SO₄) and concentrated. The crudematerial was purified by column chromatography on silica gel elutingwith EtOAc/heptane (1:6 to 1:2) to give greater than 5 g of 27 of about90% purity. This material was further purified on an Analogixchromatography system eluting with 0-30% EtOAc/heptane to give 4.3 g(35%) of 27.

Step 2. 3-(Ethoxy-d₅)-4-(methoxy-d₃)-benzaldehyde (10b): 27 (4.3 g. 27.7mmol) was mixed with Cs₂CO₃ (15 g, 46 mmol) in acetone and cooled in anice-water bath. Bromoethane-d₅ (99 atom % D, Cambridge Isotopes; 3.8 g,33.6 mmol) was added and the reaction was stirred overnight. MTBE wasadded and the mixture was filtered through a pad of Celite. Afterconcentrating, the crude product was purified by chromatography onsilica gel eluting with 1:4 EtOAc/heptane to give 2 g (38%) of thedesired 10b.

Step 3.1-(3-(Ethoxy-d₅)-4-(methoxy-d₃)-phenyl)-2-(methylsulfonyl)ethanamine(11b). Methyl sulfone (1 g, 10.7 mmol) was suspended in THF (70 mL) andcooled in an acetone/dry ice bath to below −70° C. n-BuLi (2.5 M inhexanes, 4.8 mL, 11.9 mmol) was added and the mixture was stirred about30 minutes. In a separate flask, a solution of the aldehyde 10b (2 g,10.6 mmol) in THF (20 mL) was cooled to 0° C. LHMDS (1M in THF, 12 mL)was added. After 15 minutes boron trifluoride etherate (2.8 mL, 22 mmol)was added and stirring was continued for another 5 minutes. Thissolution was then added to the methyl sulfone/n-BuLi solution, withcooling in an acetone/dry ice bath at below −70° C., via a syringe. Anexotherm was observed. This mixture was allowed to warm to roomtemperature and stirred overnight. After cooling in an ice-water bath,K₂CO₃(8 g) was added followed by water (50 mL). The layers wereseparated and the aqueous phase was extracted with EtOAc (2×20 mL). Thecombined organic solution was dried (Na₂SO₄) and concentrated to give asticky oil. MTBE (30 mL) and aqueous HCl (4N, 30 mL) were added and themixture was stirred at room temperature for 2 hr to give a clearbiphasic solution. The phases were separated and the organic phase wasextracted with aqueous HCl (4 N, 25 mL). To the combined aqueous phaseswas added aqueous NaOH (24%) to raise the pH above 12. The solution wasextracted with EtOAc (3×50 mL). The combined organic solution was dried(Na₂SO₄), and concentrated to give a yellow solid. The solid wassuspended in MTBE (20 mL) and stirred for one hour. Filtration undervacuum gave 1.2 g (38%) of 11b as a light yellow solid.

Step 4.(S)-1-(3-(Ethoxy-d₅)-4-(methoxy-d₃)-phenyl)-2-(methylsulfonyl)ethanamineN-acetyl-L-leucine salt ((S)-11b). 11b (1.05 g, 3.73 mmol) was mixedwith N-acetyl-L-leucine (0.39 g, 2.24 mmol) in MeOH (6 mL). This mixturewas heated at 70° C. for 3 hr then stirred at room temperatureovernight. The solid was collected by vacuum filtration and wassuspended in MeOH (15 mL). The suspension was stirred at 70° C. for 2 hrthen at room temperature overnight. The solid was collected and the MeOHtrituration was repeated. A 400-mg portion (23%) of (S)-11bN-acetyl-L-leucine salt was obtained with >98% ee.

Step 5.(S)—N-(2-(1-(3-(Ethoxy-d₅)-4-(methoxy-d₃)-phenyl-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide(Compound 107a): (S)-11b N-acetyl-L-leucine salt (220 mg, 0.5 mmol) wasmixed with known 12a (123 mg, 0.6 mmol) in acetic acid (5 mL) and heatedat reflux for 24 hr to drive the reaction to near completion. Themixture was concentrated, the colorless oil was dissolved in EtOAc (100mL) and the solution was washed with saturated aqueous NaHCO₃ (20 mL).The organic phase was dried (Na₂SO₄) and concentrated. The crude productpurified by column chromatography on an Analogix system eluting with0-70% EtOAc/heptane to afford 210 mg (89%) of 107a. ¹H-NMR (300 MHz,CDCl₃): δ 1.59 (s, 1H), 2.27 (s, 3H), 2.87 (s, 3H), 3.72 (dd, J=4.6,14.4, 1H), 3.85 (s, 3H), 4.56 (dd, J=10.8, 14.4, 1H), 5.87 (dd, J=4.4,10.6), 6.84 (d, J=8.8, 1H), 7.10 (d, J=7.0, 2H), 7.49 (d, J=6.6, 1H),7.65 (t, J=7.3, 1H), 8.76 (d, J=8.0, 1H), 9.46 (s, 1H). ¹³C-NMR (75 MHz,CDCl₃): δ 24.97, 41.66, 48.60, 54.55, 55.96, 76.58, 77.01, 77.43, 11.48,112.40, 115.14, 118.25, 120.29, 125.00, 129.26, 131.07, 136.14, 137.66,148.70, 149.79, 167.51, 169.17, 169.53. HPLC (method: 50 mm 3 μm WatersAtlantis T3 2.1 column—gradient method 5-95% ACN+0.1% formic acid in 14min with 4 min hold at 95% ACN+0.1% formic acid; wavelength: 305 nm);retention time: 6.02 min; >98.0% purity. Chiral HPLC (method: ChiralpakAD 25 cm column—isocratic method 78% hexane/22% isopropanol/0.01%diethylamine for 40 minutes at 1.00 mL/min; wavelength: 254 nm):retention time: 1.2.73 min (major enantiomer); >99% ee purity. MS(M+Na): 488.1. Elemental Analysis (C₂₂H₂₁D₃N₂O₇S): Calculated: C=56.76,H=5.20, N=6.02, S=6.89. Found: C=56.74, H-=5.43, N=5.70, S=6.51.

Example 3 Synthesis of(S)—N-(2-(1-(Methylsulfonyl)-1-(3-ethoxy-4-(methoxy-d₃)phenyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide(Compound 114a)

Step 1. 3-Ethoxy-4-(methoxy-d₃)-benzaldehyde (10c). A mixture ofcommercially available 16a (5 g, 30 mmol) and Cs₂CO₃ (15 g, 46 mmol) inacetone was cooled in an ice-water bath. (CD₃)₂SO₄ (99 atom % D,Cambridge Isotopes; 2.7 mL, 30 mmol) was added and the reaction wasallowed to warm slowly to mom temperature and was stirred overnight. Themixture was filtered through a pad of Celite and concentrated to give5.7 g (approx 100%) of 10c.

Step 2. 1-(3-Ethoxy-4-(methoxy-d₃)phenyl)-2-(methylsulfonyl)ethanamine(11c). Methyl sulfone (3 g, 32.1 mmol) was suspended in THF (280 mL) andcooled in an acetone/dry ice bath to below −70° C. n-BuLi (2.5 M inhexanes. 13.6 mL, 35.7 mmol) was added and the mixture was stirred about30 minutes. In a separate flask a solution of 10c (5.7 g, 30.2 mmol) inTHF (60 mL) was cooled to 0° C. LHMDS (1M in THF, 34.4 mL) was added.After 15 minutes boron trifluoride etherate (8 mL, 62.9 mmol) was addedand the mixture was stirred for 5 minutes. This solution was added tothe methyl sulfone/n-BuLi solution, with cooling in an acetone/dry icebath to below −70° C., via a syringe. An exotherm was observed. Thismixture was allowed to warm to room temperature and was stirredovernight. After cooling in an ice-water bath, K₂CO₃ (24 g) was addedfollowed by water (150 mL). The layers were separated and the aqueousphase was extracted with EtOAc (3×60 mL). The combined organic solutionwas dried (Na₂SO₄) and concentrated to give a sticky oil. MTBE (90 mL)and aqueous HCl (4N, 90 mL) were added to the residue and the mixturestirred at room temperature for 2 hr to give a clear biphasic solution.The phases were separated and the organic phase was extracted withaqueous HCl (4 N, 75 mL). To the combined aqueous phases was addedaqueous NaOH (24%) to raise the pH above 12. The aqueous layer wasextracted with EtOAc (3×150 mL). The combined organic solution was dried(Na₂SO₄) and concentrated to give a yellow solid. The solid wassuspended in MTBE (60 mL) and stirred for one hour. Filtration undervacuum gave 2.7 g (31.4%) of 11c as a light yellow solid.

Step 3.(S)-1-(3-Ethoxy-4-(methoxy-d₃)-phenyl-2-(methylsulfonyl)ethanamineN-acetyl-L-leucine salt ((S)-11c). 11c (2.3 g, 8.17 mmol) was mixed withN-acetyl-L-leucine (0.78 g. 4.48 mmol) in MeOH (12 mL). The mixture washeated at 70° C. for 3 hr then stirred at room temperature overnight.The solid was collected by vacuum filtration, suspended in MeOH (12 mL)and stirred at 70° C. for 2 hr, then at room temperature overnight. Thesolid was collected and the MeOH trituration was repeated. A 1-g portion(28.8%) of(S)-11c N-acetyl-L-leucine salt was obtained with >98% ee.

Step 4.(S)—N-(2-(1-(3-Ethoxy-4-(methoxy-d₃)-phenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide(114a). (S)-11c (0.97 g, 2.2 mmol) was mixed with known 12a (470 mg, 2.5mmol) in acetic acid (20 mL) and heated at reflux for 24 hr to drive thereaction to near completion. The mixture was concentrated, the colorlessoil was dissolved in EtOAc (200 mL) and the solution was washed withsaturated NaHCO₃ (40 mL). The organic phase was dried (Na₂SO₄) andconcentrated. The crude product was purified by column chromatography onan Analogix system eluting with 0-70% EtOAc/heptane to afford 0.7 g(68%) of 114a. ¹H-NMR (300 MHz, CDCl₃): δ 1.47 (t, J=7.0, 3H), 1.61 (s,1H), 2.26 (s, 3H), 2.87 (s, 3H), 3.72 (dd, J=4.6, 14.4, 1H), 4.11 (q,J=6.9, 14.0, 2H), 4.55 (dd, J=10.5, 14.4, 1H), 5.87 (dd, J=4.4, 10.6,1H), 6.84 (d, J=8.7, 1H), 7.10 (d, J=6.5, 2H), 7.49 (d, J=7.3, 1H), 7.65(t, J=7.7, 1H), 8.76 (d, J=8.5, 1H), 9.46 (s, 1H). ¹³C-NMR (75 MHz,CDCl₃): δ 14.70, 24.96, 41.65, 48.59, 54.54, 64.55, 111.46, 112.44,115.14, 118.25, 120.32, 125.00, 129.24, 131.07, 136.14, 137.66, 148.67,149.79, 167.51, 169.17, 169.53. HPLC (method: 50 mm 3 μm Waters AtlantisT3 2.1 column—gradient method 5-95% ACN+0.1% formic acid in 14 min with4 min hold at 95% ACN+0.1% formic acid; wavelength: 305 nm): retentiontime: 6.03 min; 97.4% purity. Chiral HPLC (method: Chiralpak AD 25 cmcolumn—isocratic method 78% hexane/22% isopropanol/0.01% diethylaminefor 40 minutes at 1.00 mL/min; wavelength: 254 nm): retention time:12.69 min (major enantiomer); 39.03 min (minor enantiomer); >99% eepurity. MS (M+Na): 486.0. Elemental Analysis (C₂₂H₂₁D₃N₂O₇S):Calculated: C=57.01, H=5.22, N=6.04, S=6.92. Found: C=57.68, H=5.63,N=5.52, S=6.33.

Example 4 Synthesis of(S)—N-(2-(2-Methylsulfonyl)-1-(3-(ethoxy-d₃)-4-(methoxy)phenyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide(Compound 110a)

Step 1. 3-(Ethoxy-d₅)-4-methoxy-benzaldehyde (10d). Commerciallyavailable 29 (5 g, 30 mmol) was mixed with Cs₂CO₃ (15 g, 46 mmol) inacetone and cooled in an ice-water bath. Bromoethane-d₅ (99 atom % D,Cambridge Isotopes; 3.8 g, 33.6 mmol) was added and the reaction wasallowed to warm slowly to room temperature and was stirred overnight.The reaction was diluted with MTBE, filtered through a pad of Celite,and concentrated to give 5.5 g (approx 100%) of 10d.

Step 2. 1-(3-(Ethoxy-d₅)-4-methoxy-phenyl)-2-(methylsulfonyl)ethanamine(11d). Methyl sulfone (2.76 g, 29.5 mmol) was suspended in THF (250 mL)and cooled in an acetone/dry ice bath to below −70° C. n-BuLi (2.5 M inhexanes, 12.5 mL, 31 mmol) was added and the mixture was stirred forabout 30 minutes. In a separate flask a solution of the aldehyde 10d(5.25 g, 27.6 mmol) in THF (50 mL) was cooled to 0° C. LHMDS (1M in THF,31.7 mL) was added. After 15 minutes boron trifluoride etherate (7.36mL, 57.8 mmol) was added and the mixture was stirred another 5 minutes.This solution was then added to the methyl sulfone/n-BuLi solution, withcooling in an acetone/dry ice bath at below −70° C., via a syringe. Anexotherm was observed. This mixture was allowed to warm to roomtemperature and was stirred overnight. After cooling in an ice-waterbath, K₂CO₃ (24 g) was added followed by water (150 mL). The layers wereseparated and the aqueous phase was extracted with EtOAc (3×60 mL). Thecombined organic solution was dried (Na₂SO₄) and concentrated to give asticky oil. MTBE (90 mL) and aqueous HCl (4N, 90 mL) were added and themixture was stirred at room temperature for 2 hr to give a clearbiphasic solution. The phases were separated and the organic phase wasextracted with aqueous HCl (4 N, 75 mL). To the combined aqueous phaseswas added aqueous NaOH (24%) to raise the pH above 12. The mixture wasextracted with EtOAc (3×150 mL). The combined organic solution was dried(Na₂SO₄), and concentrated to give a yellow solid. The solid wassuspended in MTBE (60 mL) and stirred for one hour. Filtration undervacuum afforded 2.7 g (34.2%) of 11d as a light yellow solid.

Step 3.((S)-1-(3-(Ethoxy-d₅)-4-methoxy-phenyl)-2-(methylsulfonyl)ethanamineN-acetyl L-leucine salt ((S)-11d). 11d (2.6 g, 9.33 mmol) was mixed withN-acetyl-L-leucine (0.98 g, 5.6 mmol) in MeOH (15 mL). This mixture washeated at 70° C. for 3 hr then stirred at room temperature overnight.The solid was collected by vacuum filtration and suspended in MeOH (15mL). The suspension was stirred at 70° C. for 2 hr then at roomtemperature overnight. The solid was collected and the MeOH triturationwas repeated. A 1-g portion (23%) of (S)-11d N-acetyl-L-leucine salt wasobtained with >98% ee.

Step 4.(S)—N-(2-(1-(3-(Ethoxy-d₅)-4-methoxy-phenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acetamide(110a). (S)-11d (1.4 g, 3.2 mmol) was mixed with known 12a (0.77 g, 3.84mmol) in acetic acid (20 mL) and heated at reflux for 24 hr to drive thereaction to near completion. The mixture was concentrated, the colorlessoil was dissolved in EtOAc (200 mL) and the solution was washed withsaturated NaHCO₃ (40 mL). The organic layer was dried (Na₂SO₄) andconcentrated. The crude product was purified by column chromatography onan Analogix system eluting with 0-70% EtOAc/heptane (in 1 hr) to afford1.2 g (80%) of 110a. ¹H-NMR (300 MHz, CDCl₃): δ 1.59 (s, 1H), 2.27 (s,3H), 2.87 (s, 3H), 3.72 (dd, J=4.6, 14.4, 1H), 3.85 (s, 3H), 4.56 (dd,J=10.8, 14.4, 1H), 5.87 (dd, J=4.4, 10.6), 6.84 (d, J=8.8, 1H), 7.10 (d,J=7.0, 2H), 7.49 (d, J=6.6, 1H), 7.65 (t, J=7.3, 1H), 8.76 (d, J=8.0,1H), 9.46 (s, 1H). ¹³C-NMR (75 MHz, CDCl₃): δ 24.97, 41.66, 48.60,54.55, 55.96, 76.58, 77.01, 77.43, 111.48, 112.40, 115.14, 118.25,120.29, 125.00, 129.26, 131.07, 136.14, 137.66, 148.70, 149.79, 167.51,169.17, 169.53. HPLC (method: 50 min 3 μm Waters Atlantis T3 2.1column—gradient method 5-95% ACN+0.1% formic acid in 14 min with 4 minhold at 95% ACN+0.1% formic acid; wavelength: 305 nm): retention time:6.02 min; >98.0% purity. Chiral HPLC (method: Chiralpak AD 25 cmcolumn-isocratic method 78% hexane/22% isopropanol/0.01% diethylaminefor 40 minutes at 1.00 mL/min; wavelength: 254 nm): retention time:12.73 min (major enantiomer); >99% ee purity. MS (M+Na): 488.1.Elemental Analysis (C₂₂H₂₁D₃N₂O₇S): Calculated: C=56.76, H=5.20, N=6.02,S=6.89. Found: C=56.74, H=5.43, N=5.70, S=6.51.

Example 5 Synthesis of intermediate 12b

N-(1,3-dioxo-1,3-dihydroisobenzofuran-4-yl)acetamide-d3 (12b).Commercially available 4-aminoisobenzofuran-1,3-dione 30 (5 g, 30.6mmol) was suspended in acetic anhydride-dc (98 atom % D, CambridgeIsotopes; 10 g) and heated at reflux for 3 hr, then stirred at roomtemperature overnight. The solution was cooled to 0° C. and filtered,then the solid was washed with MTBE and dried to provide 2.5 g of 12b.

Example 6 Synthesis of(S)—N-(2(1-(3-(Ethoxy-d₅)-4-(methoxy-d₃)-phenyl-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acet-d₃-amide(Compound 115a)

(S)—N-(2-(1-(3-(Ethoxy-d₅)-4-(methoxy-d₃)-phenyl)-2-(methylsulfonyl)ethyl)-1,3-dioxoisoindolin-4-yl)acet-d₃-amide(115a): (S)-11b N-acetyl-L-leucine salt (200 mg, 0.44 mmol; see Scheme5) was mixed with 12b (130 mg; see Scheme 8) in acetic acid (5 mL) andthe solution was heated at 80° C. for 20 hr. The mixture wasconcentrated and the colorless oil was re-dissolved in EtOAc (100 mL).The solution was washed with saturated aqueous NaHCO₃ (20 mL), dried(Na₂SO₄) and concentrated. The crude product was purified by columnchromatography on an Analogix system eluting with 0-70% EtOAc/heptane toprovide 174 mg (73%) of 115a. ¹H-NMR (300 MHz, CDCl₃): δ 1.55 (s, 1H),2.87 (s, 3H), 3.72 (dd, J=4.4, 14.3, 1H), 4.56 (dd, J==10.5, 14.4, 1H),5.87 (dd, J=4.4, 10.5, 1H), 6.84 (d, J=8.5, 1H), 7.10 (d, J=7.0, 2H),7.49 (d, J=7.3, 1H), 7.66 (t, J=7.5, 1H), 8.76 (d, J=8.3, 1H), 9.46 (s,1H). ¹³C-NMR (75 MHz, CDCl₃): δ 41.66, 48.61, 54.56, 76.58, 77.00,77.21, 77.43, 111.45, 112.40, 115.14, 118.26, 120.29, 125.01, 129.24,131.07, 136.15, 137.66, 148.70, 167.52, 169.54. HPLC (method: 50 mm 3 μmWaters Atlantis T3 2.1 column—gradient method 5-95% ACN+0.1% formic acidin 14 min with 4 min hold at 95% ACN+0.1% formic acid; wavelength: 305nm): retention time: 5.96 min; 99.1% purity. MS (M+H): 472.0. ElementalAnalysis (C₂₂H₁₆D₈N₇O₇S): Calculated: C=56.04, H=5.13, N=5.94. Found:C=55.90; H=5.23, N=5.85.

Example 7(S)—N-(2-(1-(3-(Ethoxy-d₅)-4-methoxy-d₃)-phenyl)-2-((methyl-d₃)-sulfonyl)-2,2-d₂-ethyl)-1,3-dioxoisoindolin-4-yl)acetamide(Compound 116a)

Step 1.1-(3-(Ethoxy-d₅)-4-(methoxy-d₃)-phenyl)-2-((methyl-d₃)-sulfonyl)-2,2-d₂-ethanamine(11e). Methyl sulfone-d₆ (99 atom % D, Isotec; 1 g, 10.0 mmol) wassuspended in THF (70 mL) and cooled in an acetone/dry ice bath to below−70° C. n-BuLi (2.5 M in hexanes, 4.4 mL, 11 mmol) was added and themixture was stirred about 30 minutes. In a separate flask, a solution ofthe aldehyde 10b (1.91 g, 10.0 mmol; see Scheme 5) in THF (20 mL) wascooled to 0° C. LHMDS (1M in THF, 11 mL) was added. After 15 minutesboron trifluoride etherate (2.8 mL, 22 mmol) was added and stirring wascontinued for another 5 minutes. This solution was added to the methylsulfone-d₆/n-BuLi solution, with cooling in an acetone/dry ice bath tobelow −70° C., via a syringe. An exotherm was observed. The mixture wasallowed to warm to room temperature and was stirred overnight. Aftercooling in an ice-water bath, K₂CO₃ (8 g) was added followed by water(50 mL). The layers were separated and the aqueous phase was extractedwith EtOAc (2×20 mL). The combined organic solution was dried (Na₂SO₄)and concentrated to give a sticky oil. MTBE (30 mL) and aqueous HCl (4N,30 mL) were added and the mixture was stirred at room temperature for 2hr to give a clear biphasic solution. The phases were separated and theorganic phase was extracted with aqueous HCl (4 N, 25 mL). To thecombined aqueous phases was added aqueous NaOH (24%) to raise the pHabove 12. The solution was extracted with EtOAc (3×50 mL). The combinedorganic solution was dried (Na₂SO₄), and concentrated to give a yellowsolid. The solid was suspended in MTBE (20 mL) and stirred for one hour.Filtration wider vacuum gave 1.2 g (37%) of 11e as a light yellow solid.

¹H NMR and LCMS showed some loss of isotopic purity alpha to thesulfone. This D-to-H exchange likely occurred during the acid/baseextraction. Use of deuterated solvents is preferred throughout theworkup.

The less isotopically pure material was dissolved in MeOD (99 atom % D,Cambridge Isotopes; 30 mL) and K₂CO₃ (0.5 g) was added. This mixture washeated at 70° C. for 6 hr and then concentrated to dryness. Fresh MeOD(30 mL) was added and the mixture heated to 70° C. overnight. The cooledsolution was diluted with EtOAc (100 mL) and the mixture was filtered.The filtrate was concentrated and re-dissolved in EtOAc (100 mL). Thesolution was washed with D₂O (99.9 atom % D, Cambridge Isotopes; 20 mL).The organic phase was dried (Na₂SO₄) and concentrated to giveapproximately 1 g of 11e with high isotopic purity restored.

Step 2.(S)-1-(3-(Ethoxy-d₅)-4-(methoxy-d₃)phenyl)-2-((methyl-d₃)-sulfonyl)-2,2-d₂-ethanamineN-acetyl-L-leucine salt ((S)-11e): 11e (630 mg, 2.2 mmol) was mixed withN-acetyl-L-leucine (0.23 g, 1.32 mmol) in MeOD (99 atom % D, CambridgeIsotopes; 6 mL). This mixture was heated at 70° C. for 3 hr then stirredat room temperature overnight. The solid was collected by vacuumfiltration and suspended in MeOH (6 mL). The mixture was stirred at 70°C. for 2 hr then at room temperature overnight. The solid was collectedand the MeOH trituration was repeated. A 300-mg portion (29%) of(S)-11eN-acetyl-L-leucine salt was obtained with >99% ee.

Step 3.(S)—N-(2-(1-(3-(Ethoxy-d₅)-4-(methoxy-d₃)-phenyl)-2-((methyl-d₃)-sulfonyl)-2,2,-d₂-ethyl)-1,3-dioxoisoindolin-4-yl)acetamide(116a); (S)-11e N-acetyl-L-leucine salt (280 mg, 0.62 mmol) was mixedwith known 12a (145 mg, 0.7 mmol) in acetic acid-d (99 atom % D,Aldrich; 5 mL) and heated to reflux for 24 hr to drive the reaction tonear completion. The mixture was concentrated and the colorless oil wasdissolved in EtOAc (100 mL). The solution was washed with NaHCO₃(20 mL),dried (Na₂SO₄) and concentrated. The crude product was purified bycolumn chromatography on an Analogix system eluting with 0-3%MeOH/CH₂Cl₂ to provide 245 mg (84%) of 116a. ¹H-NMR (300 MHz, CDCl₃): δ1.57 (s, 1H), 2.26 (s, 3H), 5.86 (s, 1H), 6.84 (d, J=6.8, 1H), 7.10 (d,J=6.8, 2H), 7.49 (d, J=6.4, 1H), 7.65 (t, J=7.9, 1H), 8.76 (d, J=8.5,1H), 9.46 (s, 1H). ¹³C-NMR (75 MHz, CDCl₃): δ 24.97, 48.43, 111.45,112.40, 115.14, 118.25, 120.28, 125.00, 129.22, 131.07, 136.14, 137.66,148.70, 149.79, 167.52, 169.17, 169.54. HPLC (method: 50 mm 3 μm WatersAtlantis T3 2.1 column—gradient method 5-95% ACN+0.1% formic acid in 14min with 4 min hold at 95% ACN+0.1% formic acid; wavelength: 305 nm):retention time: 5.97 min; 99.7% purity. MS (M+H): 474.3. ElementalAnalysis (C₂₂H₁₁D₁₃N₂O₇S): Calculated: C=55.80, H=5.11, N=5.92. Found:C=52.73, H=4.73, N=5.43.

Example Evaluation of Metabolic Stability

Microsomal Assay:

Human liver microsomes (20 mg/mL) are obtained from Xenotech, LLC(Lenexa, Kans.). β-nicotinamide adenine dinucleotide phosphate, reducedform (NADPH), magnesium chloride (MgCl₂), and dimethyl sulfoxide (DMSO)are purchased from Sigma-Aldrich.

Determination of Metabolic Stability:

7.5 mM stock solutions of test compounds are prepared in DMSO. The 7.5mM stock solutions are diluted to 12.5-50 μM in acetonitrile (ACN). The20 mg/mL human liver microsomes are diluted to 0.625 mg/mL in 0.1 Mpotassium phosphate buffer, pH 7.4, containing 3 mM MgCl₂. The dilutedmicrosomes are added to wells of a 96-well deep-well polypropylene platein triplicate. A 10 μL aliquot of the 12.5-50 μM test compound is addedto the microsomes and the mixture is pre-warmed for 10 minutes.Reactions are initiated by addition of pre-warmed NADPH solution. Thefinal reaction volume is 0.5 mL and contains 0.5 mg/mL human livermicrosomes, 0.25-1.0 μM test compound, and 2 mM NADPH in 0.1 M potassiumphosphate buffer, pH 7.4, and 3 mM MgCl₂. The reaction mixtures areincubated at 37° C., and 50 μL aliquots are removed at 0, 5, 10, 20, and30 minutes and added to shallow-well 96-well plates which contain 50 μLof ice-cold ACN with internal standard to stop the reactions. The platesare stored at 4° C. for 20 minutes after which 100 μL of water is addedto the wells of the plate before centrifugation to pellet precipitatedproteins. Supernatants are transferred to another 96-well plate andanalyzed for amounts of parent remaining by LC-MS/MS using an AppliedBio-systems API 4000 mass spectrometer. The same procedure is followedfor apremilast and the positive control, 7-ethoxycoumarin (1 μM).Testing is done in triplicate.

Data Analysis:

The in vitro t_(1/2)s for test compounds are calculated from the slopesof the linear regression of % parent remaining (ln) vs incubation timerelationship.

in vitro t _(1/2)=0.693/k

k=−[slope of linear regression of % parent remaining(ln)vs incubationtime]

Data analysis is performed using Microsoft Excel Software.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the illustrativeexamples, make and utilize the compounds of the present invention andpractice the claimed methods. It should be understood that the foregoingdiscussion and examples merely present a detailed description of certainpreferred embodiments. It will be apparent to those of ordinary skill inthe art that various modifications and equivalents can be made withoutdeparting from the spirit and scope of the invention.

We claim: 1.-26. (canceled)
 27. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selected from CH₃, CH₂D, CHD₂, and CD₃; R² is CH₃ or CD₃; R³ is CD₃; R⁴ is an ethyl group substituted with zero to five deuterium, or is a cyclopentyl group substituted with zero to nine deuterium; X is C═O; each of Y^(1a), Y^(1b), Y², Y³, Y⁴, Y⁵, Y⁷ and Y⁸ is independently selected from H and D; Y⁶ is selected from Cl, H, and D; and wherein the isotopic enrichment factor for each designated deuterium atom is at least
 3500. 28. The compound of claim 27 wherein the isotopic enrichment factor for each designated deuterium atom is at least 6333.3.
 29. The compound of claim 27, wherein Y⁶, Y⁷ and Y⁸ are the same; Y^(1a) and Y^(1b) are the same; and Y³, Y⁴ and Y⁵ are the same.
 30. The compound of claim 29, wherein the compound of Formula I is a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selected from CH₃ and CD₃; and R⁴ is selected from CH₂CH₃, CD₂CD₃, CD₂CH₃, and CH₂CD₃.
 31. The compound of claim 29, wherein the compound of Formula I is a compound of Formula Ia, having predominantly the (S) configuration at the carbon attached to Y²:

or a pharmaceutically acceptable salt thereof.
 32. The compound of claim 29, wherein the compound of Formula I is a compound of Formula Ib, having predominantly the (R) configuration at the carbon attached to Y²:

or a pharmaceutically acceptable salt thereof.
 33. The compound of claim 27, wherein Y⁶, Y and Y⁸ are the same.
 34. The compound of claim 27, wherein Y^(1a) and Y^(1b) are the same.
 35. The compound of claim 27, wherein Y³, Y⁴ and Y⁵ are the same.
 36. The compound of claim 27, wherein R¹ is CH₃ or CD₃.
 37. The compound of claim 27, wherein R⁴ is CD₂CD₃.
 38. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt of any of the foregoing, wherein the isotopic enrichment factor for each designated deuterium atom is at least
 3500. 39. A compound of claim 38, wherein the isotopic enrichment factor for each designated deuterium atom is at least 6333.3.
 40. A compound of claim 38, having predominantly the (S) configuration.
 41. A compound of claim 38, having predominantly the (R) configuration.
 42. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt of any of the foregoing, wherein the isotopic enrichment factor for each designated deuterium atom is at least
 3500. 43. The compound of claim 42 wherein the isotopic enrichment factor for each designated deuterium atom is at least
 4000. 44. The compound of claim 42 wherein the isotopic enrichment factor for each designated deuterium atom is at least
 4500. 45. The compound of claim 42 wherein the isotopic enrichment factor for each designated deuterium atom is at least
 5000. 46. The compound of claim 42 wherein the isotopic enrichment factor for each designated deuterium atom is at least
 5500. 47. The compound of claim 42 wherein the isotopic enrichment factor for each designated deuterium atom is at least
 6000. 48. The compound of claim 42, wherein the isotopic enrichment factor for each designated deuterium atom is at least 6333.3.
 49. The compound of claim 42 wherein the isotopic enrichment factor for each designated deuterium atom is at least 6466.7.
 50. The compound of claim 42 wherein the isotopic enrichment factor for each designated deuterium atom is at least
 6600. 51. The compound of claim 42 wherein the isotopic enrichment factor for each designated deuterium atom is at least 6633.3.
 52. A compound of claim 27, wherein any atom not designated as deuterium is present at its natural isotopic abundance.
 53. A composition comprising an effective amount of a compound of claim 27, or a pharmaceutically acceptable salt of said compound; and an acceptable carrier.
 54. A method of inhibiting PDE4 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 27 or a pharmaceutically acceptable salt thereof.
 55. A method of reducing TNF-α levels in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 27 or a pharmaceutically acceptable salt thereof.
 56. A method of treating a disease selected from the group consisting of psoriasis, sarcoidosis, psoriatic arthritis, Behçet's Disease, prurigo nodularis, lupus, rheumatoid arthritis, and rheumatoid spondylitis in a patient in need thereof comprising administering to the patient an effective amount of a compound of claim 27 or a pharmaceutically acceptable salt thereof.
 57. The method of claim 56, wherein the condition is psoriasis or sarcoidosis.
 58. The method of claim 57, wherein psoriasis is plaque-type psoriasis or refractory psoriasis.
 59. The method of claim 58, wherein sarcoidosis is cutaneous sarcoidosis.
 60. The method of claim 56, wherein lupus is cutaneous lupus.
 61. The method of claim 56, wherein the disease is selected from Behçet's Disease and rheumatoid arthritis. 